Cancer treatment has undergone dramatic changes in the past decade. The efficacy of imatinib (Gleevec™) in suppressing tumor growth has initiated a paradigm shift in drug development toward the use of cancer therapeutics with well-defined molecular targets. An increasing number of drugs are being developed to inhibit various mutant tyrosine kinases (TK). Notably, TKs are critical regulators of downstream signaling pathways that control tumor growth.
To date, the greatest clinical success of TK inhibitors has been in the treatment of malignancies with genomic mechanisms of TK target activation (e.g., CML and BCR-ABL, GIST and KIT). However, further research into common tumors has demonstrated a marked heterogeneity in underlying genomic mutations that activate signaling pathway proteins. This heterogeneity complicates the rapid identification of patients likely to benefit from treatment with a given targeted agent since increasing numbers of genomic loci must be analyzed for mutations. Moreover, the current generation of TK inhibitors (TKIs) may provide initial suppression of tumor growth, but may not be able to prevent relapse since secondary resistance is known to develop. This is in part due to the selective expansion of initial drug-resistant mutant TKs, which provokes new tumor growth. Further, while a TKI may successfully suppress upstream signaling pathways, resistance may develop from signaling via alternate downstream segments of signaling cascades.